Abstract
Millions of COVID-19 patients have succumbed to respiratory and systemic inflammation. Hyperstimulation of toll-like receptor (TLR) signaling is a key driver of immunopathology following infection by viruses. We found that severely ill COVID-19 patients in the Intensive Care Unit (ICU) display hallmarks of such hyper-stimulation with abundant agonists of nucleic acid-sensing TLRs present in their blood and lungs. These nucleic acid-containing Damage and Pathogen Associated Molecular Patterns (DAMPs/PAMPs) can be depleted using nucleic acid-binding microfibers to limit the patient samples’ ability to hyperactivate such innate immune receptors. Single-cell RNA-sequencing revealed that CD16 + monocytes from deceased but not recovered ICU patients exhibit a TLR-tolerant phenotype and a deficient anti-viral response after ex vivo TLR stimulation. Plasma proteomics confirmed such myeloid hyperactivation and revealed DAMP/PAMP carrier consumption in deceased patients. Treatment of these COVID-19 patient samples with MnO nanoparticles effectively neutralizes TLR activation by the abundant nucleic acid-containing DAMPs/PAMPs present in their lungs and blood. Finally, MnO nanoscavenger treatment limits the ability of DAMPs/PAMPs to induce TLR tolerance in monocytes. Thus, treatment with microfiber- or nanoparticle-based DAMP/PAMP scavengers may prove useful for limiting SARS-CoV-2 induced hyperinflammation, preventing monocytic TLR tolerance, and improving outcomes in severely ill COVID-19 patients.
Keywords: Major-biological sciences; Minor-immunology and inflammation.
【저자키워드】 Major-biological sciences, Minor-immunology and inflammation., 【초록키워드】 Treatment, viruses, Monocytes, SARS-CoV-2, Inflammation, Tolerance, proteomics, Infection, intensive care unit, lung, immunopathology, outcome, Toll-like receptor, ICU, monocyte, hyperinflammation, Lungs, phenotype, receptors, systemic inflammation, pattern, patients, RNA-sequencing, COVID-19 patients, Blood, CD16, Signaling, innate immune, Deceased, COVID-19 patient, Hyperstimulation, Ex vivo, Activation, damage, anti-viral response, agonist, hallmark, Hyperactivation, TLR, limit, ICU patient, neutralize, the patient, induce, hyperactivate, TLR stimulation, 【제목키워드】 COVID-19, Tolerance, TLR agonist, nucleic acid, binding, Activation, TLR, induce,